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Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia

Lin, L; Hindmarsh, PC; Metherell, LA; Alzyoud, M; Al-Ali, M; Brain, CE; Clark, AJL; ... Achermann, JC; + view all (2007) Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia. Clinical Endocrinology , 66 (2) 205 - 210. 10.1111/j.1365-2265.2006.02709.x. Green open access

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Abstract

Objective Familial glucocorticoid deficiency type I (FGD1) is a rare form of primary adrenal insufficiency resulting from recessive mutations in the ACTH receptor (MC2R, MC2R). Individuals with this condition typically present in infancy or childhood with signs and symptoms of cortisol insufficiency, but disturbances in the renin-angiotensin system, aldosterone synthesis or sodium homeostasis are not a well-documented association of FGD1. As ACTH stimulation has been shown to stimulate aldosterone release in normal controls, and other causes of hyponatraemia can occur in children with cortisol deficiency, we investigated whether MC2R changes might be identified in children with primary adrenal failure who were being treated for mineralocorticoid insufficiency.Design Mutational analysis of MC2R by direct sequencing.Patients Children (n = 22) who had been diagnosed with salt-losing forms of adrenal hypoplasia (19 isolated cases, 3 familial), and who were negative for mutations in DAX1 (NR0B1) and SF1 (NR5A1).Results MC2R mutations were found in three individuals or kindred (I: homozygous S74I; II: novel compound heterozygous R146H/560delT; III: novel homozygous 579-581delTGT). These changes represent severely disruptive loss-of-function mutations in this G-protein coupled receptor, including the first reported homozygous frameshift mutation. The apparent disturbances in sodium homeostasis were mild, manifest at times of stress (e.g. infection, salt-restriction, heat), and likely resolved with time.Conclusions MC2R mutations should be considered in children who have primary adrenal failure with apparent mild disturbances in renin-sodium homeostasis. These children may have been misdiagnosed as having salt-losing adrenal hypoplasia. Making this diagnosis has important implications for treatment, counselling and long-term prognosis.

Type: Article
Title: Severe loss-of-function mutations in the adrenocorticotropin receptor (ACTHR, MC2R) can be found in patients diagnosed with salt-losing adrenal hypoplasia
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/j.1365-2265.2006.02709.x
Publisher version: http://dx.doi.org/10.1111/j.1365-2265.2006.02709.x
Language: English
Additional information: © 2006 The Authors and Blackwell Publishing Ltd. Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation
Keywords: FAMILIAL GLUCOCORTICOID DEFICIENCY, RENIN-ACTIVITY, MESSENGER-RNA, ANGIOTENSIN-I, ALDOSTERONE, GENE, PLASMA, RADIOIMMUNOASSAY, UNRESPONSIVENESS, LOCALIZATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/99381
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